1. Field of the Invention
The present invention relates generally to the fields of molecular biology of cancers. More specifically, the present invention relates to a method of transcription therapy for cancers.
2. Description of the Related Art
Acute promyelocytic leukaemia (APL) is characterized b y the clonal expansion of malignant myeloid cells blocked at the promyelocytic stage of hemopoietic development.sup.1,2. APL is associated with reciprocal chromosomal translocations always involving the retinoic acid receptor-.alpha. (RAR-.alpha.) gene on chromosome 17, that variably translocates to the promyelocytic leukaemia (PML) gene on chromosome 15, or the PLZF [Promyelocytic Leukaemia Zinc Finger; ZNF145 in the Human Genome Organization (HUGO) nomenclature] gene on chromosome 11 (for brevity referred to hereafter as X genes.sup.3-10).
PML is a member of the RING finger family of proteins.sup.11. The PLZF gene encodes a transcription factor with transcriptional repressive activity, and is a member of the POK (POZ and Kruppel) family of proteins which share an N-terminal POZ motif and a C-terminal DNA binding domain made by Kruppel-like C2-H2 zinc-fingers.sup.9,12. Although structurally unrelated, promyelocytic leukaemia and promyelocytic leukaemia zinc finger heterodimerize and co-localize in the nucleus onto structures known as nuclear bodies.sup.13.
Retinoic acid receptors are members of the superfamily of nuclear hormone receptors which act as retinoic acid-inducible transcriptional activators, in their heterodimeric form with retinoid-X-receptors (RXRs), a second class of nuclear retinoid receptors.sup.14. In the absence of retinoic acid, retinoic acid receptor/Retinoid-X-Receptors heterodimers can repress transcription through histone deacetylation by recruiting nuclear receptor co-repressors (N-CoR or SMRT), Sin3A or Sin3B, which in turn form complexes with histone deacetylases (histone deacetylases 1 or 2), thereby resulting in nucleosome assembly and transcriptional repression.sup.15. Retinoic acid causes the dissociation of the co-repressors complex, and the recruitment of transcriptional co-activators to the retinoic acid receptor/retinoid-X-receptor complex, thus resulting in the activation of gene expression which induces terminal differentiation and growth arrest of cells of various histological origin including normal myeloid hemopoietic cells.sup.16,17.
The X-retinoic acid receptor-.alpha. and retinoic acid receptor-.alpha.-X fusion genes generated by the reciprocal translocation in APL encode for structurally different X-retinoic acid receptor-.alpha. and retinoic acid receptor-.alpha.-X products, co-expressed in the leukaemic blast, which differ in their X portions, but are identical in their retinoic acid receptor-.alpha. portion, and that can therefore be considered as retinoic acid receptor0.alpha. mutants.sup.3,4.
APL is uniquely sensitive to the differentiating action of retinoic acid (RA), becoming the paradigm for cancer differentiation therapy.sup.1,2,18. Unlike other APLs, leukaemias characterized by translocations between PLZF and retinoic acid receptor-.alpha. genes do not respond or respond poorly to retinoic acid, thus defining a new APL syndrome.sup.19. In these patients, resistance to retinoic acid could be conferred by the PLZF-retinoic acid receptor-.alpha. protein itself, or by the retinoic acid receptor-.alpha.-PLZF fusion protein which could function as an aberrant transcription factor since it retains part of the PLZF DNA binding domain and still binds to PLZF DNA binding sites.sup.12.
PML-retinoic acid receptor-.alpha. and PLZF-retinoic acid receptor-.alpha. are both able to bind to retinoic acid response elements (retinoic acid receptorE) as homodimers, and can form multimeric complexes with Retinoid-X-Receptors.sup.20-23. Therefore, X-retinoic acid receptor-.alpha. is thought to interfere with the normal retinoic acid receptor-.alpha./Retinoid-X-Receptor-retinoic acid pathway in a dominant negative manner through its ability to complex with Retinoid-X-Receptors, and/or through its altered DNA binding and transcriptional activities.sup.5-7,22-25. PML-retinoic acid receptor-.alpha. and PLZF-retinoic acid receptor-.alpha. can also heterodimerize with promyelocytic leukaemia and PLZF, thus acting in principle as double dominant negative oncogenic products, interfering with both X and retinoic acid receptor-.alpha./retinoid-X-receptor-retinoic acid-.alpha. pathways.sup.13,26-28.
However, promyelocytic leukaemia-retinoic acid receptor-.alpha. and PLZF-retinoic acid receptor-.alpha. proteins retain intact retinoic acid receptor-.alpha. DNA and ligand binding domains, and have an affinity for the ligand comparable to that of the wild-type retinoic acid receptor-.alpha..sup.29,30. Therefore, the molecular mechanisms by which both X-retinoic acid receptor-.alpha. molecules would be leukemogenic at physiological doses of retinoic acid, and would behave differently at pharmacological doses of retinoic acid, remains unexplained. As a more fundamental corollary, it is unclear if APL is caused by the aberrant retinoic acid-dependent transactivation of gene expression by X-retinoic acid receptor-.alpha. proteins since in this case APL should always be exacerbated by retinoic acid. On the contrary and paradoxically, retinoic acid is extremely effective in APL cases harboring promyelocytic leukaemia-retinoic acid receptor-.alpha.. Thus, the elucidation of the molecular basis of the differential responses to retinoic acid in APL, is crucial for the understanding of APL pathogenesis itself, and goes beyond simply clarifying the mechanisms which underlay retinoic acid resistance in APL.
The BCL-6 proto-oncogene is involved in diffuse large cell lymphoma and rearrangements of the BCL-6 gene are found in 30-40% of diffuse large cell lymphomas. The BCL-6 gene functions as a strong transcriptional repressor of promoters linked to its DNA target sequence. The BCL-6 gene functions as a transcriptional switch that controls germinal centre formation and altered expression of the BCL-6 gene appears to be important in lymphoma.
Until recently, the mechanism whereby oncogenes suppressed mRNA transcription of target genes was poorly understood. The enzymatic addition of acetyl groups to histones, nuclear proteins closely associated with DNA, is known to have a permissive effect for mRNA transcription.sup.15, probably by relaxing specific segments of tightly coiled DNA which facilitates binding of transcription factors.sup.61. Recently, several laboratories showed that certain oncogenes suppressed transcription of their target genes by recruiting histone deacetylases.sup.62-64 that cleaved acetyl groups from histones and blocked the DNA conformational change. Experimentally, this transcriptional blockade could be overcome by agents that inhibited the enzyme.
Earlier this year, several laboratories reported that the oncoprotein encoded by the chromosomal translocation in acute promyelocytic leukemia suppresses transcription by recruitment of a histone deacetylase.sup.65-67. Furthermore, resistance to the cytodifferentiating actions of all-trans retinoic acid in cell lines derived from patients with acute promyelocytic leukemia could be overcome by co-treatment with an inhibitor of histone deacetylase.sup.65-67. Since butyric acid was known to inhibit histone deacetylase.sup.68, sodium phenylbutyrate, a drug previously tested for treatment of thalassemia.sup.69 and certain hyperammonemic states.sup.70, was tested against promyelocytic leukemia.
The prior art is deficient in the lack of effective means of treating APL that is resistant to retinoic acid therapy. The present invention fulfills this longstanding need and desire in the art.